Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer
The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (s...
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Elsevier
2024-06-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924000547 |
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| author | Juanjuan Ye Futoshi Suizu Keiko Yamakawa Yuri Mukai Hiroyuki Yoneyama Jiro Kondo Motohiko Kato Akira Nishiyama Naohisa Yahagi Kyuichi Kadota |
| author_facet | Juanjuan Ye Futoshi Suizu Keiko Yamakawa Yuri Mukai Hiroyuki Yoneyama Jiro Kondo Motohiko Kato Akira Nishiyama Naohisa Yahagi Kyuichi Kadota |
| author_sort | Juanjuan Ye |
| collection | DOAJ |
| description | The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs. |
| format | Article |
| id | doaj-art-f3913de0323e46ddb401ad4843348eff |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-f3913de0323e46ddb401ad4843348eff2024-11-24T04:15:37ZengElsevierMolecular Therapy: Oncology2950-32992024-06-01322200812Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancerJuanjuan Ye0Futoshi Suizu1Keiko Yamakawa2Yuri Mukai3Hiroyuki Yoneyama4Jiro Kondo5Motohiko Kato6Akira Nishiyama7Naohisa Yahagi8Kyuichi Kadota9Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan; Department of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, JapanMolecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan; Corresponding author: Futoshi Suizu, Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.Molecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, JapanMolecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, JapanTME Therapeutics Inc., Minato-ku, Tokyo 105-0021, JapanDepartment of Materials and Life Sciences, Sophia University, Chiyoda-ku, Tokyo 102-8554, JapanCenter for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, JapanDepartment of Pharmacology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, JapanDivision of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, JapanMolecular Oncologic Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun 761-0793, Kagawa, Japan; Corresponding author: Kyuichi Kadota, Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.http://www.sciencedirect.com/science/article/pii/S2950329924000547MT: Regular Issuepancreatic ductal adenocarcinomaPDAColigonucleotidetumor-draining lymph nodeTDLN |
| spellingShingle | Juanjuan Ye Futoshi Suizu Keiko Yamakawa Yuri Mukai Hiroyuki Yoneyama Jiro Kondo Motohiko Kato Akira Nishiyama Naohisa Yahagi Kyuichi Kadota Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer Molecular Therapy: Oncology MT: Regular Issue pancreatic ductal adenocarcinoma PDAC oligonucleotide tumor-draining lymph node TDLN |
| title | Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer |
| title_full | Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer |
| title_fullStr | Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer |
| title_full_unstemmed | Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer |
| title_short | Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer |
| title_sort | intra tumoral administration of chst15 sirna remodels tumor microenvironment and augments tumor infiltrating t cells in pancreatic cancer |
| topic | MT: Regular Issue pancreatic ductal adenocarcinoma PDAC oligonucleotide tumor-draining lymph node TDLN |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924000547 |
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